Dementia is a brain disorder that seriously affects a person's ability to carry out normal daily activities. Among older people, Alzheimer's disease (AD) is the most common form of dementia and involves parts of the brain that control thought, memory, and language. Despite intensive research throughout the world, the causes of AD are still unknown and there is no cure. AD most commonly begins after the age of 60 with the risk increasing with age. Younger people can also get AD, but it is much less common. It is estimated that 3 percent of men and women ages 65 to 74 have AD. Almost half of those ages 85 and older may have the disease. AD is not a normal part of aging. AD is a complex disease that can be caused by genetic and environmental factors.
In 1906, Dr. Alois Alzheimer, noticed changes in the brain tissue of a woman who had died of an unusual mental illness. In her brain tissue, he found abnormal clumps (now known as amyloid plaques) and tangled bundles of fibers (now known as neurofibrillary tangles) which, today, are considered the pathological hallmarks of AD. Other brain changes in people with AD have been discovered. For example, with AD, there is a loss of nerve cells in areas of the brain that are vital to memory and other mental abilities. Scientists have also found that there are lower levels of chemicals in the brain that carry complex messages back and forth between nerve cells. AD may disrupt normal thinking and memory by blocking these messages between nerve cells.
Plaques and tangles are found in the same brain regions that are affected by neuronal and synaptic loss. Neuronal and synaptic loss is universally recognized as the primary cause in decline of cognitive function. The number of tangles is more highly correlated with cognitive decline than amyloid load in patients with AD (Albert PNAS 93:13547-13551 (1996)). The cellular, biochemical, and molecular events responsible for neuronal and synaptic loss in AD are not known. A number of studies have demonstrated that amyloid can be directly toxic to neurons (Iversen et al. Biochem. J. 311:1-16 (1995); Weiss et al. J. Neurochem. 62:372-375 (1994); Lorenzo et al. Ann NY Acad. Sci. 777:89-95 (1996); Storey et al. Neuropathol. Appl. Neurobiol. 2:81-97 (1999)), resulting in behavioral impairment. The toxicity of amyloid or tangles is potentially aggravated by activation of the complement cascade (Rogers et al. PNAS 21:10016-10020 (1992); Rozemuller et al. Res. Immunol. 6:646-9 (1992); Rogers et al. Res Immunol. 6:624-30 (1992); Webster et al. J. Neurochem. 69(1):388-98 (1997)). This suggests involvement of inflammatory processes in AD and neuronal death seen in AD (Fagarasan et al. Brain Res. 723(1-2):231-4. (1996); Kalaria et al. Neurodegeneration. 5(4):497-503 (1996); Kalaria et al. Neurobiol Aging. 17(5):687-93 (1996); Farlow Am J Health Syst Pharm. 55 Suppl. 2:S5-10 (1998)).
Evidence that amyloid β protein (Aβ) deposition causes some forms of AD was provided by genetic and molecular studies of some familial forms of AD (FAD). (See, e.g., Ii Drugs Aging 7(2):97-109 (1995); Hardy PNAS 94(6):2095-7 (1997); Selkoe J. Biol. Chem. 271(31):18295-8 (1996)). The amyloid plaque buildup in AD patients suggests that abnormal processing of Aβ may be a cause of AD. Aβ is a peptide of 39 to 42 amino acids and forms the core of senile plaques observed in all Alzheimer cases. If abnormal processing is the primary cause of AD, then familial Alzheimer's disease (FAD) mutations that are linked (genetically) to FAD may induce changes that, in one way or another, foster Aβ deposition. There are 3 FAD genes known so far (Hardy et al. Science 282:1075-9 (1998); Ray et al. (1998)). Mutations in these FAD genes can result in increased Aβ deposition.
The first of the 3 FAD genes codes for the Aβ precursor, amyloid precursor protein (APP) (Selkoe J. Biol. Chem. 271(31):18295-8 (1996)). Mutations in the APP gene are very rare, but all of them cause AD with 100% penetrance and result in elevated production of either total Aβ or Aβ42, both in model transfected cells and transgenic animals. The other two FAD genes code for presenilin 1 and 2 (PS1, PS2) (Hardy PNAS 94(6):2095-7 (1997)). The presenilins contain 8 transmembrane domains and several lines of evidence suggest that they are involved in intracellular protein trafficking. Other studies suggest that the presenilins function as proteases. Mutations in the presenilin genes are more common than in the APP genes, and all of them also cause FAD with 100% penetrance. Similar to APP mutants, studies have demonstrated that PS1 and PS2 mutations shift APP metabolism, resulting in elevated Aβ42 production (in vitro and in vivo).
Aβ formation is another target for affecting AD progression since Aβ amyloid plaques are a central pathological hallmark of the disease. Recently, it was suggested that certain NSAIDs are capable of lowering the level of Aβ42. United States Patent Application 2002/0128319 to Koo et al. discloses the use of an Aβ42 lowering amount of NSAID for treating AD. R-Flurbiprofen, which negligibly inhibits COX activity, was shown in Koo et al. to lower Aβ42 in a transgenic mouse model and CHO cells. The hope is that by lowering the level of Aβ42, the formation of the amyloid plaques central to the disease would be retarded.
A clinical trial using a therapy designed to eliminate Aβ plaques from disease patients failed despite strong evidence of efficacy in animal models (Pieffer et al. Science 298:1379 (2002)). The Aβ-lowering therapy that worked in animal models caused serious problems in humans. In view of the clinical studies, Atwood et al. (Science 299:1014 (2003)) noted that “Mounting evidence indicates that this deposition of amyloid-β may be a neuroprotective response to injury” and “These results demonstrate yet again the futility of removing a protein, amyloid-β, which has ubiquitous tissue expression, without first understanding its function(s).” Additionally, secretase inhibitors, which were designed to alter processing of APP, have turned out to be toxic compounds not likely to be suitable for chronic human use. Thus, it is not clear if reducing Aβ or Aβ42 is a realistic treatment/prevention option. Indeed, as noted recently, mutations in PS-1 associated with AD may cause the disease not through altering Aβ processing but rather by affecting calcium homeostasis (Mattson, Nature 442:385-386 (2003)).
Several epidemiological studies have reported an association between long-term use of NSAIDs, such as ibuprofen and aspirin, with reduced risk for certain malignancies and neurodegenerative processes characterized by dementia of the Alzheimer's type. A variety of explanations have been given for the reduced cancer and AD risk associated with long-term NSAID use. The primary action of NSAIDs appears to be inhibition of cyclooxygenase (COX) activity. Thus, a leading hypothesis is that NSAIDs reduce risk for certain cancers and AD by affecting the COX enzymes. Other explanations include mediation of apoptosis, modulation of growth factors, and modulation of the nuclear factor kappa B pathway (NF-κB).
U.S. Pat. No. 5,192,753 to Rogers et al. discloses the use of NSAIDs to treat AD through the inhibition of cyclooxygenase and therefore inhibition of prostaglandin synthesis. U.S. Pat. No. 5,643,960 to Brietner et al. discloses the use of COX inhibiting NSAIDs to delay the onset of AD symptoms. U.S. Pat. No. 6,025,395 to Brietner et al. relates to the use of COX inhibiting NSAIDs.
Statins have also been implicated as potential AD therapeutics by retrospective epidemiological studies. See Petanceska et al., J. Mol. Neurosci., 19:155-61 (2002). These retrospective studies indicate that statin users have a lower prevalence of developing AD. Since many possible explanations can account for the lower prevalence of AD in statin users aside from the use of statin, and combined with the fact that no statins have been approved for an AD indication, it is not certain if (and how/when) they can be used to treat AD.
In the United States alone, four million adults suffer from AD. Not only is AD significantly impacting the lives of countless families today, it is threatening to become even more of a problem as the baby boom generation matures. The economic burden of AD is estimated to cost over $100 billion a year and the average lifetime cost per patient is estimated to be $174,000. Unfortunately, there is no cure available for AD. Of the five drugs currently being used in the US for the treatment of AD, four of them—tacrine (Cognex®), donepezil (Aricept®), rivastigmine (Exelon®), and galantamine (Reminyl®)—are inhibitors of acetylcholinesterase. Another drug, memantine, was recently approved for treating moderate-to-severe AD. More recently it was reported that memantine showed efficacy in treating mild-to-moderate AD. Memantine is a NMDA receptor antagonist.
The drugs currently used for treating AD, including memantine and the acetylcholine esterase inhibitors, are marginally efficacious and have undesirable side-effects. Thus, there is a large unmet need for better and safer drugs for the treatment or prevention, or for the delay of onset, or reversal, of symptoms of AD and other neurodegenerative diseases characterized by the deposition of amyloid plaques comprising the Aβ42 peptide.
Cerebral amyloid angiopathy (CAA)—also known as cerebrovascular amyloidosis, congophilic angiopathy, and dysphoric angiopathy—is characterized by the deposition of β-amyloid in the media and adventitia of small- and medium-sized arteries (and less frequently, veins) of the cerebral cortex and leptomeninges. Widely recognized as a component of other disorders in which β-amyloid is deposited in the brain, such as AD and Down Syndrome, CAA is not associated with systemic amyloidosis, which is caused by the aggregation of proteins other than β-amyloid. Although CAA is recognized as one of the morphologic hallmarks of AD, it is often found in the brains of elderly patients who are otherwise neurologically healthy, and show no signs of dementia. However, while often asymptomatic, CAA can result in, and present as, intracranial hemorrhage (ICH), dementia, or transient neurologic events, with ICH being the most commonly observed effect of CAA. While the vast majority of CAA cases are sporadic, at least two familiar forms are known (i.e., hereditary cerebral hemorrhage with amyloidosis [HCHWA]-Dutch type and HCHWA-Icelandic type).
CAA is recognized by its characteristic pathophysiology. Specifically, the deposition of β-amyloid damages the media and adventitia of cortical and leptomeningeal vessels, leading to thickening of the basal membrane, stenosis of the vessel lumen, and fragmentation of the internal elastic lamina. This can result in fibrinoid necrosis and micro-aneurysm formation, predisposing a patient to ICH. Impaired elimination and accumulation of soluble and insoluble β-amyloid peptide likely underlies the pathogenesis and explains the link between CAA and AD.
At present, CAA can only be accurately diagnosed postmortem, hence its true incidence and prevalence is hard to quantify. However, estimates can be made based on autopsies and the incidence of ICH events. For example, a series of 400 autopsies found evidence of CAA in the brains of 18.3% of men and 28% of women aged 40-90 years. In a series of 117 autopsies of brains of patients with confirmed AD, 83% had evidence of CAA. The prevalence of CAA increases with advancing age; in some autopsy series it has been found in 5% of the brains of individuals in the seventh decade (aged 60-69), but in 50% of the brains of individuals older than 90 years.
CAA is estimated to account for up to 15% of all ICH in patients older than 60 years of age, and up to 50% of nontraumatic lobar ICH in patients older than 70 years, which, in turn, accounts for approximately 15-20 cases per 100,000 people per year. CAA and CAA-related hemorrhage are particularly common in elderly individuals with AD and middle-aged patients with Down syndrome.
The growing appreciation of the incidence of CAA in elderly individuals, both with and without AD, and in middle-aged Down syndrome patients indicates that there is a large unmet need for safe and effective drugs for the treatment, prevention, delay of onset, or reversal, of symptoms of CAA in such patients. Drugs that effectively lower Aβ42 peptide concentrations in the brains of such patients, thereby slowing or stopping the deposition of β-amyloid in the media and adventitia of small- and medium-sized arteries (and less frequently, veins) of the cerebral cortex and leptomeninges, should meet this need in these patients.
Individuals with trisomy 21, or Down syndrome (DS), develop a clinical syndrome of dementia that has the same neuropathological characteristics as described in AD patients without DS. The principle difference in AD neuropathology between individuals with DS and those without DS, is the age of onset. It is estimated that 10-25% of patients with DS develop AD-like dementia at age 40-49, 20-50% develop AD-like dementia at age 50-59, and 60-75% develop AD-like dementia when older than 60 years. AD-like dementia decreases survival in people with DS who are older than 45 years, but not ever person with DS will develop symptoms of AD-like dementia, even if, upon autopsy, their brain reveals the neuropathologic changes commonly associated with AD.
The first evidence for a link between DS and AD came when Blenner and Wong reported the isolation and identification of the same β-amyloid peptide in the meningeal vessels of individuals with either DS or AD. Glenner & Wong Biochem. Biophys. Res. Commun. 122:1131-1135 (1984). Subsequent mapping of the gene encoding the amyloid β precursor protein (APP) to chromosome 21 suggested that the extra copy of the APP gene possessed by trisomy-21 (DS) patients resulted in elevated expression of APP, which, in turn, resulted in increased levels of β-amyloid peptide and accelerated accumulation of β-amyloid plaques. Recently, the link between APP over-expression, and Aβ amyloidosis, in both DS and AD patients, has been further strengthened by the discovery of several independent duplications of the APP locus on chromosome 21 in French families with a variable, autosomal dominant phenotype between the pure AD phenotype seen in most families with APP mutations, and the cerebral hemorrhage phenotype of Dutch angiopathy associated with the APP E693Q (Dutch) mutation. These findings highlight the importance of APP gene dosage and provide strong support for the amyloid hypothesis, which postulates that accumulation of β-amyloid in the brain drives the neuropathogenesis seen in both AD and DS patients. Rovelet-Lecrux, et al. Nat. Genet. 38:24-26 (2006).
As improved health care leads to more and more DS patients surviving into middle age and beyond, there is a increasing need for safe, effective drugs to treat, slow or prevent the onset of dementia that almost inevitably occurs in aging DS patients. Drugs that effectively lower Aβ42 peptide concentrations in the brains of such patients, and thereby slow or stop the aggregation of β-amyloid plaques in these patients' brains, should meet this need, and should reduce the incidence of dementia in aging DS patients.